Homology Modeling and S1' Binding Pocket Characteristics of MMP-26†

doi:10.7503/cjcu20130811

Abstract

Abstract:

Human matrix metalloproteinase-26(MMP-26/endometase/matrilysin-2) is a newly identified MMP and its structure has not been reported. With the crystal structure of MMP-12 as structural template, the 3D structure of MMP-26 was built by homology modeling, and S₁' binding pocket characteristics was studied. Residue His233 inserted S₁' binding pocket and limited the depth of the pocket, consistent with the interme-diate size prediction. So MMP-26 belongs to intermediate-pocket MMPs. On the basis of the modeling, the interactions of inhibition GM6001 with MMP-26 were investigated. Carbonyl oxygen and hydroxyl oxygen of hydroxamic acid structure were in bidentate coordinated mode with catalytic zinc ion, which was consistent with the characteristics of hydroxamic acids MMPs inhibitors. This work suggests that molecular modeling is a useful tool to understand structure-activity relationships and provides new insight for rational inhibitor design that may distinguish MMPs with deep versus intermediate S₁' pockets.

Key words: MMP-26, Homology modeling, Molecular docking

CLC Number:

O641

TrendMD:

TU Guogang, LIU Chao, LIAO Yijing, XIONG Shengtao, LI Shaohua. Homology Modeling and S₁' Binding Pocket Characteristics of MMP-26^†[J]. Chem. J. Chinese Universities, 2014, 35(5): 1063.

Figures/Tables 7

Fig.1 Multiple sequence alignment of the MMP-26 catalytic domain with other MMPs^The secondary structure elements were taken from the crystal structure of MMP-1. The residue numbering was based on that of MMP-26. Gaps were indicated by hyphens. The S1' loop region was surrounded by a rectangle: ‘*’, identical residues in all six sequences; ‘:’, similar residues by the definition of CLUSTAL X2.

Fig.2 Ramachandran plot of MMP-26 modeled structure

Fig.3 Profile_3D score of MMP-26 modeled structure

Fig.4 Catalytic domain of MMP-26 constructed by homology modeling

Fig.5 RMSD vs time of the atoms from their initial positions during the 10 ns simulation of MMP-26(a) and GM6001(b)

Fig.6 Total potential energy changes of the system during molecular dynamics simulation

Fig.7 Binding profile of GM6001 and MMP-26^The inhibitor GM6001 is represented as a tube with atoms colored. The residues coordinating the catalytic zinc ion(green sphere) or forming hydrogen bond are represented as sticks. Coordination bonds and hydrogen bonds are represented as yellow dash line.

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Homology Modeling and S₁' Binding Pocket Characteristics of MMP-26^†

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